Propagation of Tau Misfolding from the Outside to the Inside of a Cell
Propagation of Tau Misfolding from the Outside to the Inside of a Cell
复制标题
DOI：
10.1074/jbc.m808759200
复制
发表时间：
2009-05-08
影响因子：
4.8
通讯作者：
Diamond, Marc I.
中科院分区：
文献类型：
--
作者：
Frost, Bess;Jacks, Rachel L.;Diamond, Marc I.
Tau病是以微管相关蛋白Tau在神经元和神经胶质中聚集为特征的神经退行性疾病。尽管Tau通常被认为是细胞内蛋白，但在细胞外空间中观察到Tau聚集体，并且在患者的脑脊液中容易检测到Tau肽。Tau聚集发生在许多疾病中，包括阿尔茨海默病和额颞叶痴呆。Tau病理开始于离散的疾病特异性区域，但最终涉及大脑的更大区域。目前尚不清楚Tau错误折叠的传播是如何发生的。我们假设细胞外Tau聚集体可以将错误折叠状态从细胞外传递到细胞内，类似于朊病毒。在这里，我们表明，细胞外Tau聚集体，而不是单体，被培养的细胞吸收。内化的Tau聚集体置换微管蛋白，与葡聚糖（流体相内吞作用的标志物）共定位，并诱导细胞内全长Tau的纤维化。这些细胞内原纤维能够在体外接种重组Tau单体的原纤维形成。最后，我们观察到新聚集的细胞内Tau在共培养的细胞之间转移。我们的数据表明，Tau聚集体可以从细胞的外部到内部传播纤维状的错误折叠状态。这可能对理解蛋白质错误折叠如何在tau蛋白病患者的大脑中传播具有重要意义，并且它可能与与蛋白质错误折叠相关的无数神经退行性疾病相关。
Tauopathies are neurodegenerative diseases characterized by aggregation of the microtubule-associated protein Tau in neurons and glia. Although Tau is normally considered an intracellular protein, Tau aggregates are observed in the extracellular space, and Tau peptide is readily detected in the cerebrospinal fluid of patients. Tau aggregation occurs in many diseases, including Alzheimer disease and frontotemporal dementia. Tau pathology begins in discrete, disease-specific regions but eventually involves much larger areas of the brain. It is unknown how this propagation of Tau misfolding occurs. We hypothesize that extracellular Tau aggregates can transmit a misfolded state from the outside to the inside of a cell, similar to prions. Here we show that extracellular Tau aggregates, but not monomer, are taken up by cultured cells. Internalized Tau aggregates displace tubulin, co-localize with dextran, a marker of fluid-phase endocytosis, and induce fibrillization of intracellular full-length Tau. These intracellular fibrils are competent to seed fibril formation of recombinant Tau monomer in vitro. Finally, we observed that newly aggregated intracellular Tau transfers between co-cultured cells. Our data indicate that Tau aggregates can propagate a fibrillar, misfolded state from the outside to the inside of a cell. This may have important implications for understanding how protein misfolding spreads through the brains of tauopathy patients, and it is potentially relevant to myriad neurodegenerative diseases associated with protein misfolding.